JPS6147461A - Method for obtaining aziridine-2-carboxamide - Google Patents

Abstract

PURPOSE:To obtain the aimed compound easily in high yield, by treating a reaction solution of a 2,3-dihalopropionic acid ester, etc. with ammonia with a basic anion exchange resin in isolating the titled compound useful as antitumor agents, etc. CONSTITUTION:A 2,3-dihalopropionic acid ester or amide or 2-haloacrylic acid ester or amide is reacted with ammonia to give a reaction solution containing the titled compound is used directly or cooled or concentrated, etc. to deposit an ammonium halide, etc., which is removed. The reaction solution is then brought into contact with a basic anion exchange resin to remove the above- mentioned solvent and give industrially and advantageously the titled compound in high purity. According to the method, not only halogen ions formed by the above-mentioned reaction but also anionic by-products, etc., can be removed with the above-mentioned exchange resin and the exchange resin can be recovered for reuse.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2.3-shiba01 day pion @: [sprue or amide or 2-ha[] acrylic acid T ster ()
Alternatively, aziridine can be produced by the reaction between amide and ammonia.
In the method for producing 2-carboxylic acid amide, aziridine-2=carboxylic acid amide is separated from the reaction product solution.
ll IIIt Concerning the method of armoring.

Aziridine-12 to carboxylic acid amide 1, each itself and its derivatives at σ, are compounds that play a role in l'q'I activity 14, such as anti-liver cancer, and are also used as intermediates for pharmaceuticals, agricultural chemicals, α-amino acids, etc. Body, functional layer resin? 7'7) It is a highly reactive and useful compound as a raw material.

In the conventional synthesis method of 11 quasi-aziridine-2-carboxylic acid amide, reaction from 2,3-shiba[1 pianic acid ester or amide or 2-heroacrylic acid ester or amide at -T] The only example that does this is the following: That is, this method involves the reaction of 2,3-dibromopropionic acid ester or 2-bromoacrylic acid amide with liquid ammonia (Swiss Patent No. 362,0
No. 78 (1957), and 1lelv, Chill
l, ^cta, /19°359 (1966)).

An intermediate method of preparing aziridine-2-carboxylic acid amide in this method is to prepare aziridine-2-carboxylic acid amide from the reaction solution.
This is a method in which 6L is used to crystallize the residue after extracting the stem. Although there is no description of yield G1, the recovery rate of pure aziridine-2-carboxylic acid amide during crystallization is expected to be low. By-produced annium halide and aziridine-2-carboxylic acid amide are completely separated from each other during crystallization. This is because it is difficult to do so (see Reference Example 1).

In this way, the following J, U(f aziridine-
Properties of 2-carboxylic acid amide include 1° (1) It is easily soluble in water and alcohol solvents, and cannot be extracted with organic solvents such as acetic acid nibble, J-jyl, and benzene.

(2) It is very thermally unstable and decomposes during heating operations such as distillation.

(3) By applying heating or acidic conditions in the coexistence of an inorganic salt containing a halogen ion, the aziridine ring is attacked by the halogen ion and undergoes a G-J opening reaction.

To avoid such difficulties, some conventional synthetic methods include 2,3-dibromopropionic acid ester or
There is an example in which aziridine-2-carboxylic acid amide is synthesized by dividing the reaction into two or more stages using 1-moacrylic acid amide as a raw material, and then examining intermediates throughout the day. (Chew, Bar,, 93.163
2 (1960), West German Patent (Publication) No. 2.74
No. 8,015 ('1976). However, this method has a low yield of intermediates and is far from a practical method.

! L! ! ! 117)□ ■ T like this! In order to overcome this problem, the present inventors conducted extensive studies and found that aziridine-2-carboxylic acid amide can be obtained surprisingly easily by using a basic anion exchange resin.

Therefore, the method for obtaining aziridine-2-carboxylic acid amide according to the present invention is based on the method of obtaining aziridine-2-carboxylic acid amide, such as 2,3-dihalopropionic acid ester or amide or 2-dihalopropionic acid ester or amide. A'=)1 Nodine-2 obtained from the reaction with An'TC3A From the reaction solution containing the A'=) Nodine-2-carboxylic acid amide, azinodine-2-h carboxylic acid amide was first obtained; This method is characterized in that the reaction solution is treated with a salt-based anionic acid. □−□Efficacy 1! According to Akira Motoshino, 2,3 di-8'h ``1 pyric acid ester or amide:t; The reaction solution containing the aziridine-2-carboxylic acid amine I is used as it is, or after cooling, concentration, etc., the precipitated heptadium halide is removed.
, contact with basic anion-containing 1M fat, and then dissolve it.
z m 1 m ji ct -r-;' is pure dream aziridine-2-cal-posi acid amide.

-t'l, if it is not necessary to convert the aziridine-2-'carboxylic acid amine as a crystal, of course,
Even in the state of a solution, it can be used for a variety of purposes without concentrating the solvent.

By using an anion exchange resin, not only the halogen ion formed in the reaction but also the amide can be
The removal of anionic by-products that have changed to @ can also be achieved at once, and it must be said that the effect of water droplets is tremendous.

Of course, it is possible to recover and reuse the anion exchange phase 110.

Accordingly, Kibo Moe provides a method for obtaining Ajimoe Jin-Dikal-Made Amide which is T-intensively advantageous.

The aziridine-2-carboxylic acid amide bovine liquid for use in this school is obtained from the reaction of 2,3-dihalopropionic acid ester or amide or 2-heroacrylic acid ester or amide with ammonia. With the reaction solution
Yes (see equation 1). Here, halogen refers to chlorine, bromine, or iodine.

X C) 12 C11 (';O/ or In the manufacturing method and 1 No. 1, the Swiss Special Contract No. 362,078 (1957) OJ: and He1v, Chem, Act
a, u, 359 (1966), there is a method invented by the present inventors (co-current application (1)).

The aziridine-2-carboxylic acid amide production liquid can be an aqueous solution, a solution of a lower alcohol such as methanol, ethanol, or isopropanol, a solution of dimethylformamide, dimebrus sulfoxide, hexamethylphosphoric acid triamide, etc., or a mixed solution thereof. There is no problem even in the state of

1. The basic anion exchange resin to be used may be a strong base or a strong base anion exchange resin. When using, it must be OH type.
No 3. In addition, ion exchange resin substrates [, L1 gel type, porous type, and [1. Any type of substrate such as macroporous type can be used.

Therefore, there is no particular limitation as long as it is a salt IH anion exchange resin. Preferred are strongly basic anion exchange resins. Further, there is no problem in using a combination of a strong basic anion exchange resin and a weak J-based anion exchange resin, or a combination of two or more brands of basic anion exchange resins. Moreover, a cation exchange resin can be used in combination, if necessary.

The shape of the ion exchange resin may be granular, film, or any other suitable shape. Here, "granular" means spherical,
It means granular, pellet-like, etc. [membrane-like,
; means that the composition containing the anion exchange resin or the resin is in the form of a noilum, either itself or the supporting material.
It means something in the form of a sheet, etc.

The amount of ion exchange resin used is the same for both strong basic and weak Ji-based bamboos, and is anionic by weight such as halogen ions and carboxyl groups present in the aziridine-2=carboxylic acid amide 1-acid solution. 1 for the total sum of products
．． 0.05 or higher, preferred, Schiff 1.25 or higher.

If it exceeds this value, it is acceptable to use perpendicular suspension, but it is not preferable to use light soil and efficiency above 150 equivalents. For example, aziridine-2 containing 1 mole of antnium halide, 0.3 mole of aziridine, and 2-carboxylic acid.
- Using carboxylic acid amide 11 solution, exchange capacity 1, 3
When using a granular basic anion exchange resin of meq /+nl, the amount of resin used is 1.0 liter or more, preferably 1.2 liter or more.

In addition, when the amount of resin is less than 1.0 liter, leakage of anionic by-products such as halogen ions and carboxyl groups occurs.

Operation method The method of contacting the aziridine-2-carboxylic acid amide product solution with the ion exchange resin used in the method of the present invention may be either a continuous method using a column packed with granular resin or a membrane-packed method, or a batch method. .

For example, in the case of column A method, the aziridine-2-carboxylic acid amide product solution is placed in a column filled with ion exchange resin either as it is or after being concentrated to partially precipitate and remove by-products such as ammonium halide. Pass. If desired, additional solvent may be passed through for washing. In this case, the solvent is! It is preferable to use the solvent used for the one-coat liquid preparation, but there is no particular problem even if the solvent is different from the solvent for the production liquid as long as it is water or a lower alcohol. Further, at this time, the concentration of the aziridine-2-carboxylic acid amide production solution and the amount of solvent are not particularly limited as long as the solution has fluidity.

When using a membranous ion exchange resin, use the diffusion dialysis method, 1[
All conventional methods using ion exchange membranes, such as dialysis and electrodialysis, can be used in the present invention. Here, ``diffusion dialysis'' is a method that removes impurities by the difference in the concentration of the substance to be removed on both sides of the membrane, and ``pressure dialysis'' This method creates a pressure difference on both sides of the membrane and uses this FE force difference to remove impurities. "Electrodialysis" is a method of removing impurities by applying an electric charge across the membrane.

In the present invention, a particulate ion exchange resin and a membrane ion exchange resin can also be used together.

The temperature at which the ion exchange resin is treated is not particularly limited, but is usually 0 to 60°C, preferably 10 to 40°C, taking into consideration the heat resistance temperature of the ion exchange resin.

By concentrating the solution passed through the ion exchange resin in this manner, crystals of aziridine-2-carboxylic acid amide having t4I11 traces can be easily obtained.

In order to further increase the purity rlf of hair silidin-2-carboxylic acid amide, the objective can be achieved by, for example, recrystallization.

Further, the used ion exchange resin can be regenerated and reused by carrying out a normal re-F method using a 1-lium hydroxide aqueous solution or the like.

In addition, since the crystals of aziridine-2-carboxylic acid amide that have been dissociated are thermally unstable, it is preferable to store them in a cool and dark place.

L! UL1 (Synthesis of aziridine-2-carboxylic acid amide) 2,3-dichloropropionic acid methyl ester 5. Oo (31.8 mmol)
and 22 o of isopropanol, and after sealing, fill with ammonia 22 (J (1,29 Illol)).
The reaction was carried out at 0°C for 2 hours. After the reaction, the ammonia was purged and the precipitated ammonium chloride was removed by filtration.
An isopropanol solution of aziridine-2-carboxylic acid amide was obtained. At this time, the production yield of aziridine-2-carboxylic acid amide was 82.0%. In addition, the amount of 7-F:nium chloride precipitated and removed was 2.900 (54
, 2+u+ol"), which corresponded to 85.'2% of Sokuron candy.

Concentrate the obtained isopropanol solution to □3.24
o pale yellow solid is 4q. The purity of 6-aziridine-2-carboxylic acid amide in solid is 63. 'a%.
・Support 1” - The isopropanol solution of aziridine-2-carboxylic acid amide synthesized in Reference Example 1 was filled with 15+nl of a strong base Yinken ion exchange resin (Diaio>5A-10A (O1 type)) in advance. It was passed through a column to be replaced with isopropanol, and then passed through isopropanol 501. This operation was performed at room temperature. The isopropanol was distilled off from the resulting solution under reduced pressure to obtain 2.220 crystals of aziridine-2-carboxylic acid amide.The purity of aziridine-2-carboxylic acid amide was 94.7%. -Chita (Recovery 'i'93
．． 6%).

1 store■1 □Aziridine-2-4 synthesized in Reference Example 1; isopropanol solution of human uric acid amide was filled with 90 liters of weak i-based anionic resin (Diaion WA-101). 5 columns which had been previously substituted with isopropanol were passed through the column, and 100'+ alt- -2-Carboxylic acid amide crystal 2.32
I got 0. The purity was 92.6% (recovery rate 95.
6%).

Reference Example 2 (Synthesis of aziridine-2-carboxylic acid amide) 5.00 (31,'8 smol) of 2,3-dichloropropionic acid methyl ester and 22 o of water were placed in a 3001 pressure-resistant reactor, and after sealing, ammonia 22Q ( 1,
29sol) and reacted at 60°C for 8 hours.

After the reaction, ammonia was purged to obtain an aqueous aziridine-2-carboxylic acid amide solution.

At this time, ÷ silydine-2-carboxylic acid amide yield i
was 91.6%. i'mm3 Aziridine-2-carvone Fi1i synthesized by Participant i
The 'j'mid aqueous solution was passed through a Karano\ filled with 70 ml of a strongly basic anion exchange resin (Diaion S△10Δ(OHfisu)), and then distilled water 701 was passed through. This operation was performed at room temperature. Water was removed from the aqueous solution by -C distillation under reduced pressure to obtain 2.630 crystals of aziridine-2-carboxylic acid amide. Purity was 92.0% (recovery rate 96.6%).

* PJLa (Synthesis of aziridine-2-carboxylic acid nomide) While cooling the reactor of 2001 in a dry ice bath, add liquid ammonia 730 (4.29 mol).
) was collected, and while keeping it at -30°C to -40°C, 2,3-dibromopropionic acid methyl ester 7.4
(30.1 mmol) was added dropwise for 30 minutes.Furthermore, under liquid ammonia reflux (-27°C)
After reacting for 5 hours, ammonia was distilled off. Isopropanol 501 was added to the resulting mixture, and the precipitated ammonium bromide was filtered to obtain an isopropanol solution of aziridine-2-carboxylic acid amide. At this time, the production yield of azide=15-lysine-2-carboxylic acid amide was 17.1
%Met. In addition, the precipitated and removed q-ammoniumuno 1
The suspension is 3.75!1 <38.3 mmol>,
This corresponded to 63.6% of the theoretical value.

Example 4 The isopropanol solution of aziridine-2-carboxylic acid amide synthesized in Reference Example 3 was treated with a strongly basic anion exchange resin ([Diaion 5A-10Δ] (01-1 arm) 35
Fill the solution with 1 ml and pass it through 1 ml of isopropanol, which was previously purchased, and then pass through 50 ml of isopropanol. This operation was performed at room temperature. The isopropanol was distilled off from the resulting solution under reduced pressure to obtain 1.21q of crystals of aziridine-2-carboxylic acid amide.The purity of aziridine-2-carboxylic acid amide was 93.9%. (Recovery rate 93.1%).

Claims (1)

[Claims] Aziridine-2-carboxylic acid amide is isolated from a reaction solution containing aziridine-2-carboxylic acid amide obtained by reacting a 2,3-dihalopropionic acid ester or amide or a 2-haloacrylic acid ester or amide with ammonia. Aziridine-- characterized by treating the reaction solution with a basic anion exchange resin when separating
Method for obtaining 2-carboxylic acid amide.